There are many "allergic" models of asthma available which are widely used in studies seeking to understand mechanisms of airway hyperreactivity. Although antigen challenge in these models mimics some aspects of acute human asthma, these models lack the nonspecific airway hyperreactivity, characteristic of the human disease. While studies in such models contribute to our understanding of the complexity of the immune response, they tell us little about airway hyperreactivity. This severely limits their usefulness as models. In contrast, our Basenji-Greyhound (BG) crossbred dogs demonstrate persistent nonspecific airway hyperreactivity, separate from allergy, making our model an ideal situation to elucidate mechanisms underlying airway hyperreactivity. The discovery of this dog population with persistent airway hyperreactivity is a significant advance in this field. The ability to pass on this trait to the offspring ensures a continuing supply of these animals. This provides us with a unique opportunity to understand the defect underlying airway hyperractivity in these dogs and perhaps in man, thus leading to better methods of preventing and treating a common chronic disabling disease. We have shown that airway hyperreactivity in these dogs is not directly associated with increased parasympathetic nervous system activity, increased lung epithelial permeability in the absence of airway challenge, or an intrinsic defect in the airway smooth muscle. Our studies with citric acid aerosols suggest that mediators are involved and that calcium shifts inside some airway cell are responsible for release. Preliminary data suggest anatomic abnormalities in the arrangement of muscle bundles, elastic fibers and epithelium of the airway of BG dogs. Over the next five years we plan to determine which of the possible mediators are important in airway hyperreactivity in the BG dog model of asthma. We plan to measure from the bronchoalveolar fluid many of these mediators directly and the rest by bioassay after immunological and non-immunological aerosol challenge. We plan to identify the cell in the airway from which these mediators are derived and to relate these events to a structural or functional difference in an airway cell or structure of BG compared to non-BG dogs.